CAI is now actively under investigation in 8 phase I III clinical trials through MB and CTEP. Our phase I study of CAI/paclitaxel has begun a new accrual phase wherein patients receive continuous daily dosing of CAI and have paclitaxel administered three weekly after an initial 8 days of CAI treatment. Patients will receive their CAI at bedtime daily with paclitaxel on a 3 hr infusion q 21 days. Thirteen pts have been accrued and one partial response in a pt with cervix cancer has been seen and minor responses in gastric cancer and pancreatic cancer. No new side effects have been identified in this schedule. While it was found that paclitaxel stimulated a rise in circulating CAI concentrations in a paclitaxel dose-dependent fashion in the intermittent CAI/paclitaxel schedule, no evidence of a sustained rise or cumulative rise in CAI concentrations have been observed to date in the continuous CAI arm. The phase II pharmacokinetically dosed ovarian cancer phase II study has opened and has accrued 25 pts to date. Six pts (30%) have attained the objective of 6 months of disease stabilization and the cohort is being expanded to its full number. Dosing has been individualized by pharmacokinetic parameters. At least 3 patients did not attain a stable plasma concentration of >/= 2.0 ug/ml, several have required milk to aid in absorption, and several have required dose modification for plasma concentrations above 5 ug/ml. Blood is being stored for analysis of circulating MMP-2 and VEGF concentrations. Preclinical data in a melanoma murine xenograft model has indicated a reduction in circulating IL-8 and VEGF in response to daily administration of CAI. Collaboration continues with the NEI to investigate local administration of CAI in ocular models. These are directed towards potential administration in a trial of macular degeneration. No direct ocular toxicity has been identified to date in the rabbit models.